Regulation 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (the “Regulation”)

Introduction

Traditionally, the results of clinical trials have not always been published. This is often due to an increased number of pharmaceutical companies, journals and academics being included, so greater time and money is spent producing reports of successful and interesting clinical trials. This is beginning to change with new laws in both the US and the EU requiring results to be published within a certain timeframe, regardless of the outcome of the trial. Aside from other issues surrounding data protection and confidentiality, this has sparked controversy over whether data from previous unpublished trials should now be released into the public domain.

This article covers the information currently available, the current regulatory landscape and the changes being brought in by the new legislation in the EU.

Under current legislation:

1. What information is available about clinical trials?

There are two main online databases which allow information about clinical trials to be registered, published and stored. The first is www.ClinicalTrials.gov which is maintained by the US National Institutes of Health. The website shows the study details including the sponsor and collaborators, the purpose of the study, eligibility for participants and who to contact for further information. Where a study has ended, results of the trial can also be published here. These results should give details of the reporting groups revealing what was taken at which intervals and details of participants including how many started, stopped, completed the trial and gives details of the various adverse events. The outcome measures should also be included in the results section.

The second database is http://www.ClinicalTrialsRegister.eu which is maintained by the European Medicines Agency. It shows study details, population and protocol details. It may also show results where these have been published but most examples show either no results available or results removed from public view.

2. Must results of clinical trials be published?

In the EU, clinical trial results must be reported to the competent authority responsible for licensing the drugs but there is no requirement for the results of clinical trials to be made available to the public. It is estimated that up to half of clinical trials never have their results published. There are many reasons why the results may not be published:

  • pharmaceutical companies want to highlight results of trials where their drug has been most effective, not trials where it may have been less so or ineffective;
  • journals publish interesting results, usually where the drug has worked; and
  • academics are less keen to spend time writing up results which show no effect.

A combination of these and other factors result in medicinal drugs being portrayed as more effective than they really are. This has resulted in drugs being used and causing harm where that harm could have been avoided had all of the trial data been available before authorisation or use. In 2007 the US legislature brought in legislation to combat this issue requiring the results of all trials to be published within one year of completion of data collection. This does not seem to have been strictly implemented, the Economist cites, “a report in the New England Journal of medicine combed through clinicaltrials.gov, looking to see how quickly after completion trials were reported. It found that, after the legal maximum of a year was up, just 17% of those paid for by industry had had their results published. […] Only 8.1% of trials paid for by the National Institutes of Health, […] were reported within a year. […] The Food and Drug Administration [which monitors the website] has the power to fine companies that do not comply, it has never actually done so.”

There is increasing concern about the unpublished data and pressure groups, such as the international AllTrials campaign, and lobbyists have gained significant support in their quest for all clinical trials results to be published. The WHO has stated that there is a moral, ethical and scientific obligation to register all trials. The concern however remains for historic trials for drugs which are now in circulation. Some firms, such as GlaxoSmithKline and Pfizer are now publishing historic data from previously unpublished trials. This will allow the effectiveness of drugs currently in use to be more accurately assessed and will create more transparency surrounding clinical trials giving shareholders more confidence. Other firms however, are taking no steps to publish any historic data due to concerns about data protection. Whilst participants would now be asked to consent to their data being published, the participants in historic trials may not have consented to that data being published.

What does the new EU Regulation require?

The Regulation, which will come into force in mid-2016 states at Article 37(4) that “irrespective of the outcome of a clinical trial, within one year from the end of a clinical trial in all Member States concerned, the sponsor shall submit to the EU database a summary of the results of the clinical trial.”

1. What information must be published?

The information to be published is set out in Annex IV to the Regulation and includes:

  • clinical trial information;
  • subject disposition;
  • baseline characteristics;
  • end points;
  • adverse events; and
  • additional information such as modifications and interruptions.

Further details of each is set out in Annex IV. The summary should be accompanied by a summary written in a manner that is understandable to laypersons as set out in Annex V. Where there is a scientific reason detailed in the protocol explaining why results cannot be produced within one year, the summary should be submitted as soon as it is available along with a justification.

2. What are the consequences of non-compliance with the Regulation?

The Regulation gives the power to Member States at Article 94 to lay down rules on penalties applicable to infringements of the Regulation and requires Member States to take all measures necessary to ensure they are implemented. The penalties provided for shall be effective, proportionate and dissuasive. Article 94(2) refers specifically to the penalties applying to non-compliance with the provisions on submission of information intended to be made publicly available to the EU database.

Conclusion

The Regulation has been generally well received by the industry and it is felt that increased transparency with regards to clinical trials will benefit the companies, the participants and the health of the population in general.